Abstract: Marfan syndrome (MFS) is a common disorder caused by mutations in the matrix protein fibrillin-1. Many manifestations of MFS, including aortic aneurysm and tear, are driven by excessive TGFbeta signaling, particularly the noncanonical ERK cascade, and can be attenuated by TGFbeta blocking agents in mouse models, including the FDA-approved drug losartan. It is not known if such therapies will work in people with MFS, whether individual variation will limit response to a subset, or if side effects will preclude sufficient dosing. Our understanding of how fibrillin-1 deficiency initiates altered TGFbeta activity remains incomplete, as does knowledge regarding events that culminate in tissue failure, that define particularly vulnerable patient populations such as pregnant woman with MFS or that account for the wide intrafamilial variability in the onset and severity of vascular disease seen in MFS. Answers to these questions will have direct clinical implications. Aim 1 will build upon the demonstration that a congenital presentation of skin fibrosis (scleroderma) is caused by mutations in fibrillin- that specifically impair integrin binding to its RGD sequence. Mice harboring a RGD to RGE mutation in fibrillin-1 (causing an obligate loss of integrin binding) show dense dermal fibrosis i association with increased expression of an integrin subtype (avb3) known to activate TGFbeta and ERK, and are protected from fibrosis by manipulations that mimic the interaction between fibrillin-1 and other integrins (e.g. a5b1). Our preliminary studies show that RGE mice also develop aortic aneurysm, providing an ideal system to test the hypothesis that loss of matricellular integrin-ligand interaction is an inciting event in the MFS aorta and to test integrn-targeted therapies. Aim 2 will exploit our recent observation that calcium channel blockers (CCBs) rapidly accelerate vascular disease in MFS mice. The tight temporal sequence between CCB administration and aortic tear will allow discrimination between pathogenic and compensatory events when advanced transcriptome and proteomics profiling methods are applied. Aim 3 will explore mechanism and therapy for the strong predisposition for aortic tear at the end of pregnancy or in the immediate postnatal period in pregnant women with MFS - a particularly vulnerable and understudied population. The temporal association between release of oxytocin to mediate delivery and lactation (via activation of ERK) and the timing of predisposition has implicated oxytocin as a potential mediator of cardiovascular risk. This hypothesis will be tested using both targeted genetic and drug trials. Finally, Aim 4 will define and mechanistically characterize the first identified major modifying locus for vascular disease in MFS that has been mapped to chromosome 6. These studies have the strong potential to unveil novel therapeutic targets and strategies for MFS and perhaps more common presentations of aneurysm. PUBLIC HEALTH RELEVANCE: Narrative: Using both people and mouse models with Marfan syndrome, we will explore molecular mechanisms that drive or protect from aortic aneurysm, a condition that is responsible for the death of 1-2% of all people in industrialized countries. To our knowledge, this is the firs effort to define the basis and treatment for aortic tear in pregnant women, a particularly vulnerable patient group. There is high potential that this work will derive novel treatment strategies for Marfan syndrome, and that these insights will prove relevant to other presentations of aortic aneurysm.